EINSTEIN pooled analysis

Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies (2013)

Condition

Treatment of acute symptomatic VTE

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Objective

To provide more precise estimates of efficacy and safety of rivaroxaban vs. standard treatment in patients with VTE, focusing key clinical subgroups in which VKA therapy is associated with an increase in complications, such as in patients who are elderly or renally impaired, and in those with cancer or previous VTE

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Trial design

Prespecified pooled analysis of the EINSTEIN-DVT and EINSTEIN-PE randomized phase III studies
Active treatment: rivaroxaban 15 mg p.o. twice daily for 3 weeks followed by rivaroxaban 20 mg once daily for 3, 6 or 12 months, as determined locally (n=4151)
Control treatment: enoxaparin 1.0 mg/kg s.c. twice daily for at least 5 days in combination with either warfarin or acenocoumarol (INR 2.0–3.0); enoxaparin discontinued if INR ≥2, VKA continued for 3, 6 or 12 months, as determined locally (n=4131)

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Endpoints

Primary efficacy endpoint: symptomatic recurrent VTE (defined as the composite of recurrent DVT or fatal or non-fatal PE)
Primary safety endpoint: composite of major and clinically relevant nonmajor bleeding
Secondary outcomes: major bleeding, net clinical benefit (defined as the composite of the primary efficacy outcome and major bleeding)

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Trial participants

8282 patients with symptomatic DVT and/or PE. Efficacy and safety outcomes were separately analyzed in key prespecified subgroups of patients, i.e. fragile patients (>75 years, calculated creatinine clearance <50 ml/min, or body weight ≤50 kg; n=1573), those with cancer (n=597), patients with a previous VTE (n=1610), and patients presenting with a clot burden (limited: n=1614, intermediate: n=3754, extensive: n=2691)

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Results

Efficacy outcome: 86 patients (2.1%) treated with rivaroxaban and 95 patients (2.3%) receiving the standard therapy experienced a symptomatic re-current VTE (primary efficacy outcome; HR 0.89, p<0.001 for non-inferiority). The corresponding rates for the prespecified subgroups are shown in the diagram below
Safety outcome: The primary safety endpoint, a first major or clinically relevant non-major bleeding episode, was observed in 9.4% of patients in the rivaroxaban group and 10.0% of those in the standard-therapy group (HR 0.93). For the corresponding rates for the prespecified subgroups see the diagram below
Major bleeding occurred in 1.0% of all patients treated with rivaroxaban vs. 1.7% of patients given standard therapy (HR 0.54). The composite of recurrent VTE and major bleeding (net clinical benefit) was significantly improved in patients treated with rivaroxaban, occurring in 3.2% of patients in the rivaroxaban group as compared with 4.1% in the standard-therapy group (HR 0.77)

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Summary

Efficacy: The fixed-dose regimen of oral rivaroxaban is at least as effective for the treatment of acute symptomatic VTE as the standard therapy with subcutaneous enoxaparin and INR-titrated VKA
Safety: The bleeding rates were similar in the two study groups, with significantly fewer major bleeding events in the rivaroxaban group
Efficacy and safety results were consistent amongst key patient subgroups. Particularly in those patients in whom VKA therapy is associated with an increase in complications, use of rivaroxaban resulted in an important safety advantage

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Reference

Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Raskob GE, Berkowitz SD, Wells PS; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013;11:21; doi: 10.1186/1477-9560-11-21

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Corresponding author

Martin H Prins, MD PhD, Maastricht University Medical Center, P.O. Box 616, 6200 MD Maastricht, The Netherlands, e-mail: mh.prins@epid.unimaas.nl

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